A major effort in the laboratory is devoted to understanding dystonia. Our fundamental view is that there is a deficiency of inhibition in central nervous system mechanisms in dystonia. Specifically, an important type of defective inhibition is surround inhibition, where muscles and movements not desired for the task need to be inhibited. Lack of inhibition leads to motor overflow and action dystonia. We are trying to identify the specific inhibitory circuit that contributes to surround inhibition. Studies are first done in normal subjects and then in patients. We have investigated a variety of inhibitory mechanisms already, and we are now engaged in understanding the premotor to motor cortex interactions and parietal to motor cortex interactions in focal hand dystonia. Evidence developed in the past year suggests that the mechanism of surround inhibition actually arises from the connections within the motor cortex itself. We are also exploring the physiology of motor learning in dystonia. Motor learning seems disturbed, and seems to have a principal role in producing focal hand dystonia since long term repetitive activity is certainly an etiological factor. In one type of experiment, we have been evaluating brain and spinal cord plasticity using brain and nerve stimulation paradigms. We have concluded a case-control experimental study to evaluate long-term learning of sequential finger movements in focal hand dystonia patients, and are analyzing the data now. In order to study task specificity, we have done fMRI studies with various tasks and various limb effectors. Specifically we studied patients with writers cramp. We have found that task specificity relies on a parietal-premotor pathway and this is deficient in patients. To gather further evidence for abnormalities in dystonia we are also exploring evidence for anatomical changes and for a deficiency of GABA-ergic mechanism. We are doing MRI studies with voxel based morphometry (VBM), diffusion tensor imaging (DTI), GABA magnetic resonance spectroscopy (MRS), anatomical imaging at 7 tesla, flumazenil PET studies and pathological studies of brains of patients with dystonia. The genetic markers in focal dystonia are largely unknown. Currently, we are evaluating patients with all forms of focal dystonia (blepharospasm, cranial dystonia, cervical dystonia, focal hand dystonia and spasmodic dysphonia) to look for a genetic marker. The study involves large families with focal dystonia and individuals without a family history. We have collaborators in the NIA for the genetics work. We are cooperating with the multisite NIH sponsored Dystonia Coalition for work in this area. We are also exploring further the physiology of Parkinson disease (PD). Although the sequence effect, the gradual reduction in size of movement, is one of the most common symptom in PD, its characteristics and etiology are largely unknown. With objective measurement, we have completed some studies of the clinical features and the lack of beneficial effect of levodopa and repetitive transcranial magnetic stimulation, and we are now evaluating the behavioral features in more detail. Future plans call for a neuroimaging investigation. We are also studying gait freezing that, at least in some circumstances, relates to the sequence effect.